Journal of Inherited Metabolic Disease最新文献

{"title":"Integration of multi-omics layers empowers precision diagnosis through unveiling pathogenic mechanisms on maple syrup urine disease","authors":"Juan Ramón Tejedor,&nbsp;Alejandro Soriano-Sexto,&nbsp;Leonardo Beccari,&nbsp;Natalia Castejón-Fernández,&nbsp;Patricia Correcher,&nbsp;Lidia Sainz-Ledo,&nbsp;Juan José Alba-Linares,&nbsp;Rocío G. Urdinguio,&nbsp;Magdalena Ugarte,&nbsp;Agustín F. Fernández,&nbsp;Pilar Rodríguez-Pombo,&nbsp;Mario F. Fraga,&nbsp;Belén Pérez","doi":"10.1002/jimd.12829","DOIUrl":"10.1002/jimd.12829","url":null,"abstract":"<p>Maple syrup urine disease (MSUD) is a rare inherited metabolic disorder characterized by deficient activity of the branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex, required to metabolize the amino acids leucine, isoleucine, and valine. Despite its profound metabolic implications, the molecular alterations underlying this metabolic impairment had not yet been completely elucidated. We performed a comprehensive multi-omics integration analysis, including genomic, epigenomic, and transcriptomic data from fibroblasts derived from a cohort of MSUD patients and unaffected controls to genetically characterize an MSUD case and to unravel the MSUD pathophysiology. MSUD patients exhibit a defined episignature that reshapes the global DNA methylation landscape, resulting in the stimulation of HOX cluster genes and the restriction of cell cycle gene-related signatures. Subsequent data integration revealed the impact of AP1-related and CEBPB transcription factors on the observed molecular reorganization, with MEIS1 emerging as a potential downstream candidate affected by robust epigenetic repression in MSUD patients. Furthermore, the integration of multi-omics layers facilitated the identification of a strong epigenetic repression in the <i>DBT</i> promoter in a patient wherein no BCKDH pathogenic variants had been detected. A Circular Chromatin Conformation Capture assay indicated a disturbance of the interactions of <i>DBT</i> promoter, thereby unveiling alternative modes of disease inheritance. Integration of multi-omics data unveiled underlying molecular networks rewired in MSUD patients and represents a powerful approach with diagnostic potential for rare genetic disorders with unknown genetic bases.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulatory response to exercise relative to oxygen uptake assessed in the follow-up of patients with fatty acid beta-oxidation disorders","authors":"Apolline Imbard,&nbsp;Hortense de Calbiac,&nbsp;Edouard Le Guillou,&nbsp;Pascal Laforêt,&nbsp;Manuel Schiff,&nbsp;Anaïs Brassier,&nbsp;Elise Thevenet,&nbsp;Clément Pontoizeau,&nbsp;Bertrand Lefrère,&nbsp;Chris Ottolenghi,&nbsp;Elise Lebigot,&nbsp;Pauline Gaignard,&nbsp;Stéphanie Gobin,&nbsp;Cécile Acquaviva-Bourdain,&nbsp;Jean-François Benoist,&nbsp;Caroline Tuchmann-Durand,&nbsp;Antoine Legendre,&nbsp;Pascale de Lonlay","doi":"10.1002/jimd.12819","DOIUrl":"10.1002/jimd.12819","url":null,"abstract":"<p>Patients with fatty acid oxidation disorders (FAODs) experience muscle symptoms due to impaired ATP metabolism and the toxicity of accumulated mitochondrial FAO substrates or intermediates, especially during catabolic states. A major issue is the absence of specific and sensible biomarkers to evaluate metabolic equilibrium. The relationship between cardiac output (Q) and oxygen consumption (VO₂) during incremental exercise (dQ/dVO₂) provides an indirect surrogate of mitochondrial function. A high dQ/dVO₂ slope indicates impaired oxidative phosphorylation in skeletal muscle during exercise. Our study aimed to evaluate dQ/dVO₂ as a potential marker of the severity of FAODs. We retrospectively collected clinical, laboratory parameters and treatment data for FAOD patients over 6 years old, including a disease severity score, plasma acylcarnitines and cardiopulmonary exercise tests with Q measurement via thoracic bioelectrical impedance. FAO flux was measured in whole blood and in myoblasts when available. We included 27 FAOD patients followed from 2015 to 2022, with deficiencies in LCHAD (<i>n</i> = 10), CPT2 (<i>n</i> = 6), VLCAD (<i>n</i> = 7), or MADD (<i>n</i> = 4). CPT2 deficient patients with severe scores had the highest C18:1-, C16-, C18-acylcarnitines, and dQ/dVO₂. In these patients, dQ/dVO₂ was positively correlated with C18:1, C16, and C18 acylcarnitines. In a linear multivariate regression model, dQ/dVO₂ was significantly associated with the severity score (B = 0.831, <i>p =</i> 0.008) and triheptanoin treatment (B = −0.547, <i>p =</i> 0.025). dQ/dVO₂ and plasma long-chain acylcarnitines might be useful to monitor CPT2D, as these parameters associate with our clinical severity score and could reflect altered mitochondrial functions.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imaging readiness in the gene therapy era-exploring standardized protocols for response assessment","authors":"Asthik Biswas,&nbsp;Audrey K. S. Soo,&nbsp;Manju A. Kurian,&nbsp;Ulrike Löbel,&nbsp;Felice D'Arco,&nbsp;Spyros Batzios,&nbsp;Sniya Sudhakar,&nbsp;Kshitij Mankad,&nbsp;the IMaging Assessment in Gene and Enzyme Replacement therapies (IMAGER) study group","doi":"10.1002/jimd.12828","DOIUrl":"10.1002/jimd.12828","url":null,"abstract":"","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical severity and cardiac phenotype in phosphomannomutase 2-congenital disorders of glycosylation : Insights into genetics and management recommendations","authors":"Veronika Holubova,&nbsp;Rita Barone,&nbsp;Stephanie Grunewald,&nbsp;Markéta Tesařová,&nbsp;Hana Hansíková,&nbsp;Jana Augustínová,&nbsp;Jolanta Sykut-Cegielska,&nbsp;Francesca De Nictolis,&nbsp;Unai Diaz-Moreno,&nbsp;Ramyia Elangovan,&nbsp;Florencia Epifani,&nbsp;Serena Gasperini,&nbsp;Mirian Jansen,&nbsp;Dirk Lefeber,&nbsp;Dorota Maksym-Gasiorek,&nbsp;Martinelli Diego,&nbsp;Katrin Ounap,&nbsp;Fabio Pettinato,&nbsp;Haide Põder,&nbsp;Daisy Rymen,&nbsp;Mari-Anne Vals,&nbsp;Mercedes Serrano,&nbsp;Peter Witters,&nbsp;Tomáš Honzík","doi":"10.1002/jimd.12826","DOIUrl":"10.1002/jimd.12826","url":null,"abstract":"<p>Cardiac involvement (CI) in phosphomannomutase 2-congenital disorders of glycosylation (PMM2-CDG) is part of the multisystemic presentation contributing to high mortality rates. The most common cardiac manifestations are pericardial effusion, cardiomyopathy, and structural heart defects. A genotype–phenotype correlation with organ involvement has not yet been described. We analyzed clinical, biochemical, and molecular genetic data of 222 patients from eight European centers and characterized the natural course of patients with CI. Fifty-seven patients (45 children) presented with CI, of whom 24 died (median age 21 months, standard deviation 49.8). Pericardial effusion was the most frequent manifestation (55.4%), occurring mostly within the first 6 months of life. The most common pathogenic variants in patients with CI were p.(Arg141His) in 74%, followed by p.(Val231Met) in 36%, which is 3.5 times higher than in PMM2-CDG patients without CI (<i>p</i> &lt; 0.0001). Twenty-one out of 36 patients with p.(Val231Met) had CI; among them, 15 died, compared to 33 out of 166 patients without p.(Val231Met) who had CI (<i>p</i> &lt; 0.0001). Nine out of 33 patients died (<i>p</i> = 0.0015), indicating greater clinical severity. Furthermore, the p.(Val231Met) variant is predominant in Eastern Europe, suggesting a founder effect. Cardiac complications in PMM2-CDG patients are common and serious. The variant p.(Val231Met) profoundly influences the extent of CI and mortality rates. Therefore, we recommend cardiac surveillance be included in the follow-up protocols for PMM2-CDG.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping challenges in the accessibility of treatment products for urea cycle disorders: A survey of European healthcare professionals","authors":"Nina N. Stolwijk,&nbsp;Johannes Häberle,&nbsp;Hidde H. Huidekoper,&nbsp;Margreet A. E. M. Wagenmakers,&nbsp;Carla E. M. Hollak,&nbsp;Annet M. Bosch,&nbsp;the E-IMD and MetabERN Working Group on the Real-World Use of products for UCD Management","doi":"10.1002/jimd.12815","DOIUrl":"10.1002/jimd.12815","url":null,"abstract":"<p>Current management guidelines for urea cycle disorders (UCDs) offer clear strategies, incorporating both authorized and non-authorized medicinal products (including intravenous formulations and products regulated as food). These varying product categories are subject to specific accessibility challenges related to availability, reimbursement, and pricing. The aim of this study is to identify potential obstacles to optimal UCD treatment implementation in European clinical practice. A survey aimed at metabolic healthcare professionals (HCPs) managing patients with UCDs in Europe was disseminated through the European Reference Network for Hereditary Metabolic Disorders and the European registry and network for intoxication type metabolic diseases. Forty-eight survey responses were collected from 21 European countries. In 16 of these countries, at least one metabolic HCP reported challenges in accessing UCD products. Reimbursement issues were reported for most products (8/10), including both authorized and non-authorized products. Availability-related challenges were also reported for 8/10 products, although unavailability was limited to non-authorized products. Prices impacted accessibility for all authorized products (3/3) and one non-authorized IV product. The accessibility of UCD treatment products varied across Europe, although no clear regional variations could be discerned. Survey data revealed that metabolic HCPs experience challenges in accessing both authorized and non-authorized products for UCD management in the majority of European countries. This indicates that registering unauthorized products may not resolve all issues. Improved reimbursement policies and fair pricing models, as well as (adjusted) authorization procedures may help address these concerns, thereby optimizing treatment access for UCD patients.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reversible white matter changes following a 4-week high phenylalanine exposure in adults with phenylketonuria","authors":"Raphaela Muri,&nbsp;Murray Bruce Reed,&nbsp;Stephanie Maissen-Abgottspon,&nbsp;Roland Kreis,&nbsp;Michel Hochuli,&nbsp;Rupert Lanzenberger,&nbsp;Roman Trepp,&nbsp;Regula Everts","doi":"10.1002/jimd.12823","DOIUrl":"10.1002/jimd.12823","url":null,"abstract":"<p>Alterations in brain structure are frequently observed in adults with early-treated phenylketonuria (PKU) compared to healthy controls, with cerebral white matter (WM) being particularly affected. The extent to which temporary elevation of phenylalanine (Phe) levels impacts WM remains unclear. We conducted a double-blind, randomised, placebo-controlled crossover trial to investigate the effects of a 4-week high Phe exposure on cerebral WM and its relationship to cognitive performance and metabolic parameters in adults with PKU. In this study, 27 adults with early-treated classical PKU (aged 19–48 years) underwent diffusion tensor imaging (DTI) before and after the 4-week Phe and placebo interventions. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were analysed using tract-based spatial statistics. Neuropsychological examinations at each timepoint evaluated executive functions and attention. Additionally, brain Phe levels were measured using MR spectroscopy, and blood levels of Phe, tyrosine, and tryptophan were assessed after an overnight fast. Following the Phe period, significant decreases in AD, MD, and RD were observed compared to the placebo period, particularly in the posterior corona radiata and optic radiation. Notably, these WM changes were reversible in patients who first received Phe (<i>n</i> = 13). Cognitive performance and metabolic parameters were not significantly related to DTI scalars after the Phe period. In conlcusion, a 4-week Phe elevation induced reversible microstructural alterations in cerebral WM. Further investigation is necessary to determine the clinical implication of these changes.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uncommon case of mitochondrial disease: Mild amyotrophy of the legs and symmetrical lipomatosis of the arms","authors":"Leslie Bercu,&nbsp;Patrizia Amati-Bonneau,&nbsp;Valérie Desquiret-Dumas,&nbsp;Vincent Procaccio,&nbsp;François Maillot","doi":"10.1002/jimd.12820","DOIUrl":"10.1002/jimd.12820","url":null,"abstract":"&lt;p&gt;A 42-year-old woman was investigated for exercise intolerance. She already had a medical follow-up because of a hypokinetic dilated cardiomyopathy identified at the age of 28 years and a chronic kidney disease, both secondary to a malignant hypertension episode. She complained about muscle pain and dyspnea on exertion, and was limited to a walking range of 200 m. She also experienced postexercise muscle pain. On clinical examination, no strength deficit was noted. She had mild amyotrophy of lower limbs and a symmetrical lipomatosis of her proximal upper limbs (Figure 1). No other localizations of lipomatosis were noted. Blood tests showed CK 1165 UI/L (26–192) and troponin 58.5 ng/L (3–14). The plasma redox cycle showed fasting lactate of 3 mmol/L, postprandial lactate up to 5.9 mmol/L along with a lactate/pyruvate ratio &gt;20. Genetic tests revealed the presence of the pathogenic mitochondrial DNA (mtDNA) mutation m.8363A&gt;G (MT-TK)&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; with a 45% mutant load in blood.&lt;/p&gt;&lt;p&gt;This case illustrates that lipomatosis can be a feature of mitochondrial disease, as shown by Musumeci et al., who reviewed 1300 patients reported in the database of the nationwide Italian Collaborative Network of Mitochondrial Disease.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; In this study, lipomatosis has been identified in 22 (1.7%) patients with primary mitochondrial disease. Interestingly, lipomatosis could be the sole manifestation of pathogenic mtDNA mutations. Among them, two patients carried the same mtDNAcm.8363 A&gt;G variant as our patient, 18 harbored the m.A8344G&gt;A variant and 2 patients had multiple deletions. Moreover, in a family study and a literature review, Virgilio et al. showed that mitochondrial DNA m.8363A&gt;G mutation in the tRNALys gene was associated with a heterogeneous disease phenotype, including some rare cases of lipomas.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; As described in our clinical case, lipomatosis associated with mtDNA mutations is usually distributed in the upper body, affecting arms, shoulders, neck, and thoracic region.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; As multiple symmetric lipomatosis has a low prevalence of 1:25 000 in the general population and is a rare feature of mitochondrial disease, the case described here illustrates a very rare situation. Thus, it seems advisable to recommend mtDNA sequencing from blood and urine samples, mostly when the clinical picture is evocative of a mitochondrial disease, as in our observation. Regarding pathophysiology, Guallar et al. have shown that lipomatosis due to tRNA(Lys) mutations was associated with a pattern of altered expression of master regulators of adipogenesis consistent with enhanced proliferation of adipocytes, and with a distorted pattern of brown versus white adipocyte differentiation.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; In our case, such pattern could not be demonstrated because we did not perform any biopsy of the lipomas (considered as being nonrelevant for diagnosis).&lt;/p&gt;&lt;p&gt;To date, there is ","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142729657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The clinical utility in hospital-wide use of growth differentiation factor 15 as a biomarker for mitochondrial DNA-related disorders","authors":"Andrea Cortés Fernández,&nbsp;Jane Estrella,&nbsp;Devin Oglesbee,&nbsp;Austin A. Larson,&nbsp;Johan L.K. Van Hove","doi":"10.1002/jimd.12821","DOIUrl":"10.1002/jimd.12821","url":null,"abstract":"<p>Clinical recognition of primary mitochondrial disorders (PMD) is difficult due to the clinical and genetic heterogeneity. Whereas lactate has low sensitivity and specificity, in structured clinical studies growth differentiation factor 15 (GDF15) has shown promise with elevations in mitochondrial DNA (mtDNA)-related PMD, but its specificity has been questioned. In a tertiary care hospital-wide study, medical records were retrospectively reviewed from 418 cases where GDF15 levels were obtained by clinicians. Patients were classified into patients with PMD due to mtDNA-related defects (mtDNA maintenance, mtDNA deletions, and mtDNA-encoded tRNA variants), PMD due to structural defects or other nuclear causes, and in non-mitochondrial disease. Patients with liver disease or systemic critical illness were excluded. GDF15 was assayed in a clinical laboratory with a cutoff of 750 ng/L. There were 38 mtDNA-related PMD (GDF15 &gt;750 pg/mL in 76%), 35 other nuclear DNA-encoded PMD or structural subunits (31% elevated GDF15), 309 non-mitochondrial disorders (13% elevated GDF15). Based on the highest Youden J-index, the optimal cut-off value to identify these target mtDNA-related disorders was 815 pg/mL, with sensitivity 76%, specificity 88%, positive predictive value of 41% and negative predictive value of 97%. At this optimized cutoff level, mtDNA-encoded PMD patients had elevated GDF15 in 76%, nuclear DNA-encoded PMD in 26%, and non-mitochondrial disorders in 11% of patients. Thus, in a real-life clinical setting, after excluding abnormal liver function and critical illness, GDF15 had good clinical utility increasing the odds at predicting mtDNA-related primary mitochondrial disorders 14-fold, but not for structural or other nuclear-encoded primary mitochondrial disorders.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epidemiology and economic burden of Wilson disease in France: A nationwide population-based study","authors":"Shona Fang,&nbsp;Martina Furegato,&nbsp;Jessica Azzi,&nbsp;Eduardo Couchonnal-Bedoya,&nbsp;Dominique Debray","doi":"10.1002/jimd.12822","DOIUrl":"10.1002/jimd.12822","url":null,"abstract":"<p>Wilson disease (WD) is a rare inherited copper metabolism disorder characterized by progressive pathological deposition of copper, primarily in the liver and brain. This longitudinal retrospective study conducted using the French national claims (Système National des Données de Santé [SNDS]) database assessed WD prevalence in France, described patients' characterizations and healthcare resource use and associated costs. Patients with WD were identified from SNDS using the International Classification of Diseases, 10th Revision code E83.0 for copper metabolism disorder or a long-term disease (affection de longue durée [ALD]) associated with this code between 2010 and 2019. Patients were categorized into hepatic, neurological, and psychiatric sub-cohorts. We identified 2287 patients with WD yielding a crude prevalence of 1 case per 33 898 individuals in 2019. The mean age at inclusion was 39.9 (standard deviation [SD] 22.8) years, 11 years more than that of the incident cohort (28.6, SD 20.3) identified via ALD, and 1180 (51.6%) patients were male. The crude mortality was 3.2% (in total 370 patients died). Overall, 1011 (44.2%), 754 (33.0%), and 414 (18.1%) patients experienced hepatic, neurological, and psychiatric manifestations, respectively. In total, 922 (40.3%) patients were reimbursed for WD-specific treatment, the most common being D-penicillamine (74.8%), and 201 (8.8%) underwent liver transplantation. The average annual hospitalization cost per patient was 4273.7€ (SD 11916.0). At least one sick leave was reported for 533 (23.3%) patients, with an annual average cost of 788.7€ (SD 1328.6). Our findings provide an updated understanding of the prevalence of WD, and indicate a considerable level of morbidity in this population, as well as a high level of direct/indirect costs associated with WD.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"My path to citrin deficiency","authors":"John E. Walker","doi":"10.1002/jimd.12818","DOIUrl":"10.1002/jimd.12818","url":null,"abstract":"<p>Citrin belongs to the SLC25 transport protein family found mostly in inner mitochondrial membranes. The family prototype, the ADP–ATP carrier, delivers ATP made inside mitochondria to the cellular cytoplasm and returns ADP to the mitochondrion for resynthesis of ATP. In pre-genomic 1981, I noticed that the protein sequence of the bovine ADP–ATP carrier consists of three related sequences, each containing two transmembrane α-helices traveling in opposite senses. Colleagues and I demonstrated that two other mitochondrial carriers had similar features. From emergent genomic sequences, it became apparent that they represented a large family of transport proteins with the same characteristic threefold repeats. The human genome encodes 53 members, but the functions of many were unknown. So, colleagues and I determined how to make these proteins in <i>Escherichia coli</i> and introduce them into liposomes to allow exploration of their transport functions. The 27 human family members to have been thus identified include citrin and the closely related protein aralar. Both exchange aspartate from the mitochondrial matrix for cytosolic glutamate plus a proton. Citrin is expressed predominantly in liver and non-excitable tissues, whereas aralar is the dominant form in the brain. Each has a membrane extrinsic N-terminal Ca²⁺-binding domain, a transport domain, and a C-terminal amphipathic α-helix. Human mutations in citrin impair the urea cycle, malate–aspartate shuttle, gluconeogenesis, amino acid breakdown, and energy metabolism leading to citrin deficiency. Currently, the complex etiology of this condition is poorly understood and new knowledge would help to improve diagnosis, therapies, and finding a cure. My aims are to seek a basic understanding of the etiology of citrin deficiency and to use that knowledge in improving diagnostic procedures and in developing new treatments and a cure.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670154/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}